Bicyclic heterocyclic compounds

ABSTRACT

The bicyclic heterocyclic compounds are prepared by reaction of correspondingly substituted carboxylic acids with amines, in particular with phenylglycinolamine. The bicyclic heterocyclic compounds according to the invention are suitable as active compounds in medicaments, in particular in medicaments having an antiatherosclerotic action.

The present invention relates to bicyclic heterocyclic compounds,processes for their preparation and their use in medicaments, inparticular as antiatherosclerotic medicaments.

It is known that increased blood levels of triglycerides(hypertriglyceridaemia) and cholesterol (hypercholesterolaemia) areassociated with the origin of atherosclerotic changes to the vascularwall and coronary heart disease.

Moreover, a significantly increased risk of developing coronary heartdisease exists if these two risk factors occur in combination, which inturn is accompanied by excessive production of apolipoprotein B-100.There is therefore still a great need to provide active medicaments forcombating atherosclerosis and coronary heart disease.

Benzimidazole derivatives having a PAF-antagonistic action furthermoreare described in U.S. Pat. No. 5,314,880.

The present invention relates to bicyclic heterocyclic compounds of thegeneral formula (I) ##STR1## in which A represents a radical of theformula ##STR2## wherein L and M are identical or different and denote

hydrogen, halogen, trifluoromethyl, carboxyl, cycloalkyl having 3 to 6carbon atoms, hydroxyl, phenyl or straight-chain or branched alkyl,alkoxycarbonyl or alkoxy having in each case up to 6 carbon atoms,

Q denotes a nitrogen atom or the --CH group,

T denotes a group of the formula --SO₂ or --CO or an oxygen or sulphuratom,

V denotes an oxygen or sulphur atom,

R⁵, R⁶, R⁷ and R⁸ are identical or different and denote

hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms,benzyl or phenyl, which are optionally substituted by halogen or bystraight-chain or branched alkyl having up to 6 carbon atoms,

R⁹ denotes trifluoromethyl, benzyl or a 5- to 7-membered, optionallybenzo-fused heterocyclic radical having up to 3 heteroatoms from theseries consisting of S, N and/or O, which is optionally substituted upto 3 times in an identical or different manner by halogen, phenyl,hydroxyl or by straight-chain or branched alkyl or alkoxy having in eachcase up to 4 carbon atoms, or denotes

a group of the formula --S(O)_(a) --R¹⁰,

wherein

a denotes the number 0, 1 or 2,

R¹⁰ denotes straight-chain or branched alkyl or alkenyl having in eachcase up to 8 carbon atoms, which are optionally substituted bystraight-chain or branched acyl having up to 6 carbon atoms or by arylor aroyl having in each case up to 10 carbon atoms, which in turn can besubstituted up to twice in an identical or different manner by halogen,trifluoromethyl or by straight-chain or branched acyl having up to 5carbon atoms, or denotes

aryl having 6 to 10 carbon atoms, which is optionally substituted byhalogen, hydroxyl, trifluoromethyl or straight-chain or branched alkylor alkoxy having in each case up to 5 carbon atoms,

D and E are identical or different and represent

hydrogen, halogen, trifluoromethyl, hydroxyl or carboxyl, or representstraight-chain or branched alkyl, alkoxy or alkoxycarbonyl having ineach case up to 6 carbon atoms,

Z represents an oxygen or sulphur atom,

R¹ represents cycloalkyl having 3 to 10 carbon atoms, or representsstraight-chain or branched alkyl having 1 to 10 carbon atoms, orrepresents

phenyl, which is optionally substituted up to twice in an identical ordifferent manner by halogen, nitro, cyano, hydroxyl or straight-chain orbranched alkyl or alkoxy having in each case up to 4 carbon atoms,

R² represents hydrogen or straight-chain or branched alkyl having up to3 carbon atoms,

R³ represents hydrogen or straight-chain or branched alkyl having up to5 carbon atoms, or represents

cycloalkyl having 3 to 7 carbon atoms, or represents phenyl, orrepresents a 5- to 7-membered aromatic heterocyclic radical having up to3 heteroatoms from the series consisting of S, N and/or O, which areoptionally substituted up to 3 times in an identical or different mannerby halogen, nitro, phenyl, hydroxyl or by straight-chain or branchedalkyl or alkoxy having up to 6 carbon atoms,

R⁴ represents hydrogen, or represents a group of the formula --CH₂ --OHor CH₂ O--CO--R¹¹,

wherein

R¹¹ denotes hydrogen, straight-chain or branched alkyl having up to 8carbon atoms or phenyl, which is optionally substituted up to 3 times inan identical or different manner by halogen, hydroxyl, cyano orstraight-chain or branched alkyl or alkoxy having in each case up to 4carbon atoms,

and salts thereof.

The bicyclic heterocyclic compounds according to the invention can alsobe in the form of their salts. Salts with organic or inorganic bases oracids may be mentioned in general here.

Physiologically acceptable salts are preferred in the context of thepresent invention. Physiologically acceptable salts of the compoundsaccording to the invention can be salts of the substances according tothe invention with mineral acids, carboxylic acids or sulphonic acids.Particularly preferred salts are, for example, those with hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid,benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid,propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid,maleic acid or benzoic acid.

Physiologically acceptable salts can likewise be metal or ammonium saltsof the compounds according to the invention which have a free carboxylgroup. Particularly preferred salts are, for example, sodium, potassium,magnesium or calcium salts, as well as ammonium salts which are derivedfrom ammonia or organic amines, such as, for example, ethylamine, di- ortriethylamine, di- or triethanolamine, dicyclohexylamine,dimethylaminoethanol, arginine, lysine, ethylenediamine or2-phenylethylamine.

The compounds according to the invention can exist in stereoisomericforms which either behave as mirror images (enantiomers) or do notbehave as mirror images (diastereomers). The invention relates both tothe enantiomers or diastereomers and to the particular mixtures thereofThese mixtures of the enantiomers and diastereomers can be separatedinto the stereoisomerically uniform constituents in a known manner.

In the context of the invention, a heterocyclic radical, which isoptionally benzo-fused, in general represents a saturated or unsaturated5- to 7-membered, preferably 5- or 6-membered, heterocyclic radicalwhich can contain up to 3 heteroatoms from the series consisting of S, Nand/or O and, in the case of a nitrogen atom, can also be bonded viathis. Examples which may be mentioned are: indolyl, quinolyl, benzob!thienyl, benzo b!furyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl,oxazolyl, imidazolyl, morpholinyl or piperidyl. Quinolyl, furyl, pyridyland thienyl are preferred.

Preferred compounds of the general formula (I) are those in which

A represents a radical of the formula ##STR3## wherein L and M areidentical or different and denote

hydrogen, fluorine, chlorine, bromine, trifluoromethyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, hydroxyl, phenyl or straight-chainor branched alkyl, alkoxycarbonyl or alkoxy having in each case up to 5carbon atoms,

Q denotes a nitrogen atom or the --CH group,

T denotes a group of the formula --SO₂ or --CO or an oxygen or sulphuratom,

V denotes an oxygen or sulphur atom,

R⁵, R⁶, R⁷ and R⁸ are identical or different and denote

hydrogen, straight-chain or branched alkyl having up to 5 carbon atoms,benzyl or phenyl, which are optionally substituted by fluorine,chlorine, bromine or by straight-chain or branched alkyl having up to 5carbon atoms,

R⁹ denotes trifluoromethyl, benzyl, benzothienyl, thienyl, pyridyl,quinolyl, imidazolyl, furyl, pyrryl, oxazolyl or thiazolyl, which areoptionally substituted up to 3 times in an identical or different mannerby fluorine, chlorine, bromine, phenyl, hydroxyl or by straight-chain orbranched alkyl or alkoxy having in each case up to 3 carbon atoms, ordenotes

a group of the formula --S(O)_(a) --R¹⁰,

wherein

a denotes the number 0 or 1,

R¹⁰ denotes straight-chain or branched alkyl or alkenyl having in eachcase up to 6 carbon atoms, which are optionally substituted bystraight-chain or branched acyl having up to 5 carbon atoms or byphenyl, benzoyl or naphthyl, which in turn can be substituted up totwice in an identical or different manner by fluorine, chlorine,bromine, trifluoromethyl or by straight-chain or branched acyl having upto 4 carbon atoms, or denotes naphthyl or phenyl, which are optionallysubstituted by fluorine, chlorine, bromine, hydroxyl, trifluoromethyl orstraight-chain or branched alkyl or alkoxy having in each case up to 4carbon atoms,

D and E are identical or different and represent

hydrogen, fluorine, chlorine, bromine, trifluoromethyl, hydroxyl orstraight-chain or branched alkyl or alkoxy having in each case up to 4carbon atoms,

Z represents an oxygen or sulphur atom,

R¹ represents cyclobutyl, cyclopentyl, cyclohexl, cycloheptyl orcyclooctyl, or represents straight-chain or branched alkyl having up to7 carbon atoms, or represents

phenyl, which is optionally substituted by fluorine, chlorine, bromine,nitro, cyano, hydroxyl or straight-chain or branched alkyl or alkoxyhaving in each case up to 3 carbon atoms,

R² denotes hydrogen or methyl,

R³ represents hydrogen or straight-chain or branched alkyl having up to4 carbon atoms, benzyl, cyclopropyl, cyclopentyl or cyclohexyl, orrepresents phenyl, pyridyl, thienyl or furyl, which are optionallysubstituted up to twice in an identical or different manner by fluorine,chlorine, bromine, phenyl, nitro, hydroxyl or by straight-chain orbranched alkyl or alkoxy having up to 4 carbon atoms,

R⁴ represents hydrogen, or represents a group of the formula --CH₂ --OHor --CH₂ O--CO--R¹¹,

wherein

R¹¹ denotes hydrogen, straight-chain or branched alkyl having up to 6carbon atoms or phenyl, which is optionally substituted up to twice inan identical or different manner by fluorine, chlorine, bromine, cyano,hydroxyl or straight-chain or branched alkyl or alkoxy having in eachcase up to 3 carbon atoms,

and salts thereof.

Particularly preferred compounds of the general formula (I) are those inwhich

A represents a radical of the formula ##STR4## wherein L and M areidentical or different and denote hydrogen, fluorine, chlorine, bromine,hydroxyl, phenyl or straight-chain or branched alkyl or alkoxy having ineach case up to 4 carbon atoms,

Q denotes a nitrogen atom or the --CH group,

T denotes a group of the formula --SO₂ or --CO or an oxygen or sulphuratom,

V denotes an oxygen or sulphur atom,

R⁵, R⁶, R⁷ and R⁸ are identical or different and denote

hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms,benzyl or phenyl, which are optionally substituted by fluorine,chlorine, bromine or by straight-chain or branched alkyl having up to 4carbon atoms,

R⁹ denotes trifluoromethyl, benzyl, benzothienyl, thienyl, pyridyl,imidazolyl, furyl or thiazolyl, which are optionally substituted up to 3times in an identical or different manner by fluorine, chlorine,bromine, phenyl, hydroxyl or by straight-chain or branched alkyl oralkoxy having in each case up to 3 carbon atoms, or denotes

a group of the formula --S(O)_(a) --R¹⁰,

wherein

a denotes the number 0 or 1,

R¹⁰ denotes straight-chain or branched alkyl or alkenyl having in eachcase up to 5 carbon atoms, which are optionally substituted bystraight-chain or branched acyl having up to 4 carbon atoms or byphenyl, benzoyl or naphthyl, which in turn can be substituted up totwice in an identical or different manner by fluorine, chlorine,bromine, trifluoromethyl or by straight-chain or branched acyl having upto 3 carbon atoms, or denotes

naphthyl or phenyl, which are optionally substituted by fluorine,chlorine, bromine, hydroxyl, trifluoromethyl or straight-chain orbranched alkyl or alkoxy having in each case up to 3 carbon atoms,

D and E are identical or different and represent hydrogen, fluorine,chlorine, bromine or trifluoromethyl,

Z represents oxygen,

R¹ represents cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, orrepresents straight-chain or branched alkyl having up to 6 carbon atoms,

R² represents hydrogen or methyl,

R³ represents phenyl and

R⁴ represents the group --CH₂ --OH,

and salts thereof

A process has furthermore been found for the preparation of thecompounds of the general formula (I) according to the invention,

characterized in that

acids of the general formula (II) ##STR5## in which A, D, E, Z and R¹have the meaning given,

are reacted with compounds of the general formula (III) ##STR6## inwhich R², R³ and R⁴ have the meaning given,

in inert solvents and in the presence of bases and/or auxiliaries.

The process according to the invention can be illustrated by way ofexample by the following equation: ##STR7##

Suitable solvents here are inert organic solvents which do not changeunder the reaction conditions. These include ethers, such as diethylether or tetrahydrofuran, halogenated hydrocarbons, such as methylenechloride, chloroform, carbon tetrachloride, 1,2-dichloroethane,trichloroethane, tetrachloroethane, 1,2-dichloroethane ortrichloroethylene, hydrocarbons, such as benzene, xylene, toluene,hexane, cyclohexane or petroleum fractions, nitromethane,dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acidtriamide. It is also possible to employ mixtures of the solvents.Methylene chloride, tetrahydrofuran, toluene or dimethylformamide areparticularly preferred.

Inorganic or organic bases can in general be employed as bases for theprocess according to the invention. These include, preferably, alkalimetal hydroxides, such as, for example, sodium hydroxide or potassiumhydroxide, alkaline earth metal hydroxides, such as, for example, bariumhydroxide, alkali metal carbonates, such as sodium carbonate orpotassium carbonate, alkaline earth metal carbonates, such as calciumcarbonate, or alkali metal or alkaline earth metal alcoholates, such assodium or potassium methanolate, sodium or potassium ethanolate orpotassium tert-butylate, or organic amines (trialkyl(C₁ -C₆)amines),such as triethylamine, or heterocyclic compounds, such as1,4-diazabicyclo 2.2.2!octane (DABCO), 1,8-diazabicyclo5.4.0!undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine ormorpholine. It is also possible to employ alkali metals, such as sodium,and hydrides thereof such as sodium hydride, as bases. Sodium carbonate,potassium carbonate and triethylamine are preferred.

The base is employed in an amount of 1 mol to 5 mol, preferably 1 mol to3 mol, per mole of the compound of the general formula (II).

Dehydrating reagents are also suitable auxiliaries. These include, forexample, carbodiimides, such as diisopropylcarbodiimide,dicyclohexylcarbodiimide orN-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, orcarbonyl compounds, such as carbonyldiimidazole, or 1,2-oxazoliumcompounds, such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphonate, orpropanephosphoric anhydride or iso-butyl chloroform ate orbenzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate orphosphonic acid diphenyl ester-amide or methanesulphonyl chloride, ifappropriate in the presence of bases, such as triethylamine orN-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiimide andN-hydroxysuccinimide.

The reaction is in general carried out in a temperature range from 0° C.to 150° C., preferably from +20° C. to +110° C.

The reaction can be carried out under normal, increased or reducedpressure (for example 0.5 to 5 bar). It is in general carried out undernormal pressure.

The compounds of the general formula (II) are new in most cases and canbe prepared, for example, by a process in which compounds of the generalformula (IV)

    A--H                                                       (IV)

in which

A has the meaning given, are reacted with compounds of the generalformula (V) ##STR8## in which D, E, Z and R¹ have the meaning given,

R¹³ represents halogen, preferably chlorine or bromine,

and

R¹⁴ represents straight-chain or branched alkyl having up to 6 carbonatoms, in inert solvents and in the presence of bases and/orauxiliaries, and, finally, the esters are hydrolysed by customarymethods.

Customary organic solvents which do not change under the reactionconditions are suitable for the reaction. These include, preferably,ethers, such as diethyl ether, dioxane, tetrahydrofuran or glycoldimethyl ether, or hydrocarbons, such as benzene, toluene, xylene,hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons,such as methylene chloride, chloroform, carbon tetrachloride,dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate,triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide,hexamethylphosphoric acid triamide, acetonitrile, acetone ornitromethane. It is also possible to use mixtures of the solventsmentioned. Dimethylformamide, tetrahydrofuran and dimethyl sulphoxideare preferred.

Bases which can be employed are in general the abovementioned bases, butin particular the alkali metal hydrides, such as sodium hydride.

The base is in general employed in an amount of 0.05 mol to 10 mol,preferably 1 mol to 2 mol, per mole of the compound of the formula (IV).

The auxiliary is in general employed in an amount of 0.01 mol to 100mol, preferably 0.1 mol to 10 mol, per mole of the compound of thegeneral formula (IV).

The reaction is in general carried out in a temperature range from -30°C. to +100° C., preferably -10° C. to +60° C.

The reaction is in general carried out under normal pressure. However,it is also possible to carry out the processes under increased pressureor under reduced pressure (for example in a range from 0.5 to 5 bar).

The above mentioned dehydrating reagents are suitable auxiliaries.

The various amine/amide derivatives are also prepared using a largenumber of known methods, such as, for example, coupling of acidderivatives from peptide chemistry in this context, cf. Bodanszky, ThePractice of Peptide Synthesis: Springer Verlag, Volume 21, 1984 andOrganic Chemistry; Functional Group Transformations: Academic Press,Volume 12-1!.

The ester hydrolysis is carried out by customary methods, by treatingthe esters with customary bases in inert solvents.

Suitable bases are the customary inorganic bases. These include,preferably, alkali metal hydroxides or alkaline earth metal hydroxides,such as, for example, sodium hydroxide, potassium hydroxide or bariumhydroxide, or alkali metal carbonates, such as sodium carbonate orpotassium carbonate or sodium bicarbonate. Sodium hydroxide or potassiumhydroxide are particularly preferably employed.

Suitable solvents are water or the organic solvents customary forhydrolysis. These include, preferably, alcohols, such as methanol,ethanol, propanol, isopropanol or butanol, or ethers, such astetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulphoxide.Alcohols, such as methanol, ethanol, propanol or isopropanol, areparticularly preferably used. It is also possible to employ mixtures ofthe solvents mentioned.

The ester hydrolysis is in general carried out in a temperature rangefrom 0° C. to +100° C., preferably from +20° C. to +80° C.

The ester hydrolysis is in general carried out under normal pressure.However, it is also possible to carry out the hydrolysis under reducedpressure or under increased pressure (for example from 0.5 to 5 bar).

In carrying out the ester hydrolysis, he base is in general employed inan amount of 1 to 3 mol, preferably 1 to 1.5 mol, per mole of the ester.Molar amounts of the reactants are particularly preferably used.

The compounds of the general formula (III) are known per se.

The compounds of the general formula (I) according to the invention havea pharmacological action spectrum which cannot be foreseen.

They can be used as active compounds in medicaments for reducing changesto vascular walls and for treatment of coronary heart disease, cardiacinsufficiency, disturbances in cerebral performance, ischaemic cerebraldiseases, apoplexy, circulatory disturbances, disturbances inmicrocirculation and thromboses.

The proliferation of smooth muscle cells, furthermore, plays a decisiverole in the occlusion of vessels. The compounds according to theinvention suitable for inhibiting this proliferation and therefore forpreventing atherosclerotic processes.

The compounds according to the invention are distinguished by areduction in ApoB-100-associated lipoproteins (VLD and its breakdownproducts, such as, for example, LDL), ApoB-100, triglycerides andcholesterol. They therefore have valuable pharmacological propertieswhich are superior to the prior art.

Suprisingly, the action of the compounds according to the inventioninitially comprises a reduction in or complete inhibition of theformation and/or release of ApoB-100-associated lipoproteins fromhepatic cells, which results in a lowering of the plasma VLDL level.This lowering in VLDL must be accompanied by a lowering of the plasmalevel of ApoB-100, LDL, triglycerides and cholesterol; several of theabovementioned risk/factors which contribute to changes to the vascularwall are thus reduced simultaneously.

The compounds according to the invention can therefore be employed forprevention and treatment of atherosclerosis, obesity, pancreatitis andconstipation.

1. Inhibition of the release of ApoB-100-associated lipoproteins

The test for detection of the inhibition of the release ofApoB-100-associated lipoproteins from hepatic cells was carried out invitro with cultured hepatic cells, preferably with cells of the humanline HepG2. These cells are cultured under standard conditions in mediumfor culture of eukaryotic cells, preferably in RPMI 1640 with 10% foetalcalf serum. HepG2 cells synthesize and secrete into the culturesupernatant ApoB-100-associated lipoprotein particles, which are inprinciple built up similarly to the VLDL and LDL particles which are tobe found in plasma.

These particles can be detected with an immunoassay for human LDL. Thisimmunoassay is carried out with antibodies which have been inducedagainst human LDL in rabbits under standard conditions. The anti-LDLantibodies (rab-anti-LDL-Ab) were purified by affinity chromatography onan immunosorbent with human LDL. These purified rab-anti-LDL-Ab areadsorbed onto the surface of plastic. This adsorption is expedientlycarried out on the plastic surface of microtiter plates with 96 wells,preferably on MaxiSorp plates. If ApoB-100-associated particles arepresent in the supernatant of Hep-G2 cells, these can bond to theinsolubilized rab-anti-LDL-Ab, and an immune complex bonded to theplastic surface is formed. Non-bonded proteins are removed by washing.The immune complex on the plastic surface is detected with monoclonalantibodies, which have been induced against human LDL and purified understandard conditions. These antibodies were conjugated with the enzymeperoxidase. Peroxidase converts the colourless substrate TMB into acoloured product in the presence of H₂ O₂. After acidification of thereaction mixture with H₂ SO₄, the specific absorption of light isdetermined at 450 nm, this being a measure of the amount ofApoB-100-associated particles which had been secreted by the HepG2 cellsinto the culture supernatant.

Surprisingly, the compounds according to the invention inhibit therelease of ApoB-100-associated particles. The IC₅₀ value indicates theconcentration of substance at which the absorption of light is inhibitedby 50% compared with the control (solvent control without thesubstance).

    ______________________________________                                                       Apo B                                                                 Example No.                                                                           IC.sub.50  nM!                                                 ______________________________________                                                1      44.4                                                                   2      38.1                                                                   3      11.6                                                                   4      298.5                                                                  5      36.0                                                                   6      8.0                                                                    7      150.3                                                                  8      4.7                                                                    9      2.8                                                                   10      9.5                                                                   11      4.7                                                                   12      12.6                                                                  13      14.3                                                                  14      130.2                                                                 18      930.2                                                                 19      387.6                                                                 20      248.3                                                                 23      147.1                                                                 24      16.3                                                                  25      7.3                                                                   26      4.5                                                                   27      90.9                                                                  28      27.9                                                                  29      9.3                                                                   30      111.7                                                                 31      7.3                                                                   32      5.3                                                                   33      5.3                                                                   34      26.6                                                                  35      11.2                                                                  36      9.1                                                                   37      3.6                                                                   38      36.3                                                                  39      81.7                                                                  40      69.0                                                                  41      10.6                                                                  42      11.2                                                                  43      5.3                                                                   44      11.3                                                                  47      18.8                                                                  48      6.3                                                                   49      3.6                                                                   50      17.9                                                                  51      5.7                                                                   52      517.9                                                                 53      1694.9                                                                54      60.2                                                                  55      19.5                                                                  57      5.0                                                                   58      251.0                                                                 59      29.2                                                                  60      9.7                                                                   61      38.9                                                                  62      122.9                                                                 63      5.9                                                                   67      27.4                                                                  68      70.6                                                                  70      58.8                                                                  71      29.                                                                   72      392.9                                                                 73      29.4                                                                  76      37.2                                                                  77      14.9                                                                  78      279.3                                                                 79      15.2                                                                  80      7.5                                                                   81      8.5                                                            ______________________________________                                    

2. Determination of VLDL secretion in vivo on the hamster

The effect of the test substances on VLDL secretion in vivo isinvestigated on the hamster. For this, after premedication with atropine(83 mg/kg s.c.), golden hamsters are anaesthetized with Ketavet (83mg/kg s.c.) and Nembutal (50 mg/kg i.p.). When the animals have becomereflex-free, the v. jugularis is exposed and cannulated. 0.25 ml/kg of a20% strength solution of Triton WR-1339 in physiological saline solutionis then administered. This detergent inhibits lipoprotein lipase andthus leads to an increase in the triglyceride level because of anabsence of catabolism of secreted VLDL particles. This increase intriglycerides can be used as a measure for the rate of VLDL secretion.Blood was taken from the animals by puncture of the retroorbital venousplexus before and one and two hours after administration of thedetergent. The blood is incubated at room temperature for 2 hours andthen at 4° C. overnight in order to conclude coagulation completely.Thereafter, it is centrifuged at 10,000 g for 5 minutes. Thetriglyceride concentration in the serum thus obtained is determined withthe aid of a modified commercially obtainable enzyme test (Merckotest®Triglyceride No. 14354). 100 μl of test reagent are added to 100 μl ofserum in 96-well plates and the plates are incubated at room temperaturefor 10 minutes. The optical density is then determined at a wavelengthof 492 nm in an automatic plate reader (SLT-Spectra). Serum sampleshaving a triglyceride concentration which is too high are diluted withphysiological saline solution. The triglyceride concentration containedin the samples is determined with the aid of a standard curve measuredin parallel. In this model, test substances are administered eitherintravenously immediately before administration of the detergent ororally or subcutaneously before initiation of the anaesthesia.

3. Inhibition of intestinal tiglycende absorption in vivo (rats)

The substances which are to be investigated in vivo for their inhibitingaction on triglyceride absorption are administered orally to male Wistarrats having a body weight of between 170 and 230 g. For this purpose,the animals are divided into groups of 6 animals 18 hours beforeadministration of the substance, and their food is then withdrawn.Drinking water is available to the animals ad libitum. The animals ofthe control groups are given an aqueous tragacanth suspension or atragacanth suspension which comprises olive oil. The tragacanth-oliveoil suspension is prepared with an Ultra-Turrax. The substances to beinvestigated are suspended in a corresponding tragacanth-olive oilsuspension, likewise with an Ultra-Turrax, directly beforeadministration of the substance.

Before administration by a stomach tube, blood is taken from each rat bypuncture of the retroorbital venous plexus for determination of thebasal serum triglyceride content. The tragacanth suspension, thetragacanth-olive oil suspensions without a substance (control animals)or the substances, suspended in a corresponding tragacanth olive oilsuspension, are then administered to the fasting animals using a stomachtube. Further blood for determination of the postprandial serumtriglyceride increase is as a rule taken 1, 2 and 3 hours after theadministration by stomach tube.

The blood samples are centrifuged and, after isolation of the serum, thetriglycerides are determined photometrically with an EPOS-Analyzer 5060(Eppendorf Geratebau, Netheler & Hinz GmbH, Hamburg. The triglyceridesare determined completely enzymatically with a commercially available UVtest.

The postprandial increase in serum triglycerides is determined bysubtraction of the triglyceride prevalue of each animal from itscorresponding postprandial triglyceride concentrations (1, 2 and 3 hoursafter administration).

The average is taken of the differences (in mmol/l) at each point intime (1, 2 and 3 hours) in the groups, and the means of the increase inserum triglycerides (ΔTG) of the animals treated with the substance arecompared with the animals which received only the tragacanth-oilsuspension.

The chronological change in serum triglyceride in the control animals,which were given only tragacanth, is also calculated. The effect of thesubstance at each point in time (1, 2 or 3 hours) is determined asfollows and stated in Δ% of the oil-loaded control. ##EQU1##

Effect of 10 mg of test substance/kg of body weight p.o. on the increasein triglycerides (Δ%) 2 hours after a triglyceride loading in the serumof fasting rats. The increase in serum triglycerides of fat-loadedcontrol animals, based on the serum triglyceride level of tragacanthcontrol animals, corresponds to 100%. n=6 animals per group.

The statistical analysis is carried out with the Student t-test afterfirst checking the variances for homogeneity.

Substances which statistically significantly (p<0.05) reduce thepostprandial increase in serum triglyceride by at least 30%, comparedwith the untreated control group, at a point in time are regarded aspharmacologically active.

    ______________________________________                                                      Inhibition of intestinal absorption                             Example No.   of triglycerides in vivo (rats)                                 ______________________________________                                         3            2           mg/kg                                                5            2-3         mg/kg                                                6            <3          mg/kg                                                8            >6          mg/kg                                                9            2-4         mg/kg                                               10            3           mg/kg                                               21            >6          mg/kg                                               22            7           mg/kg                                               26            10          mg/kg                                               29            >/=3        mg/kg                                               30            >>10        mg/kg                                               32            3-6         mg/kg                                               33            2           mg/kg                                               34            >6          mg/kg                                               38            >2          mg/kg                                               39            2           mg/kg                                               40            >>6         mg/kg                                               41            >>2         mg/kg                                               44            >2          mg/kg                                               45            3           mg/kg                                               46            >>2         mg/kg                                               48            3           mg/kg                                               51            >>10        mg/kg                                               52            3           mg/kg                                               54            6           mg/kg                                               57            2           mg/kg                                               60            6           mg/kg                                               64            >>10        mg/kg                                               68            >10         mg/kg                                               70            >>2         mg/kg                                               74            >>2         mg/kg                                               77            8           mg/kg                                               ______________________________________                                    

4. Inhibition of VLDL secretion in vivo (rats)

The action of the test substances on VLDL secretion is also investigatedon the rat. For this, 500 mg/kg body weight (2.5 mg/kg) of TritonWR-1339, dissolved in physiological saline solution, is administeredintravenously into the tail vein of rats. Triton WR-1339 inhibitslipoprotein lipase and thus leads to an increase in the triglyceride andcholesterol level due to inhibition of VLDL catabolism. These increasescan be used as a measure of the rate of VLDL secretion.

Blood is taken from the animals by puncture of the retroorbital venousplexus before and one and two hours after administration of thedetergent. The blood is incubated at room temperature for 1 hours, forcoagulation, and the serum is isolated by centrifugation at 10,000 g for20 seconds. The triglycerides are then determined photometrically at awavelength of 540 nm by means of a commercially available coupled enzymetest (Sigma Diagnostics®, No. 339). Measurement is carried out with theaid of a similarly coupled enzyme test (Boehringer Mannheim®, No.1442350) at a wavelength of 546 nm. Samples with triglyceride orcholesterol concentrations which exceed the measurement range of themethods are diluted with physiological saline solution. The particularserum concentrations are determined with the aid of standard seriesmeasured in parallel. Test substances are administered orally,intravenously or subcutaneously immediately after the Triton injection.

The invention furthermore relates to the combination of bicyclicheterocyclic compounds of the general formula (I) with a glucosidaseand/or amylase inhibitor for treatment of familial hyperlipidaemias,obesity (adiposity) and diabetes mellitus. Glucosidase and/or amylaseinhibitors in the context of the invention are, for example, acarbose,adiposine, voglibose (AO-128), miglitol, emiglitate, MDL-25637,camiglibase (MDL-73945), temdamistate, AI-3688, trestatin, pradimicin-Qand salbostatin. The combination of acarbose, miglitol, emiglitate orvaglibose with one of the abovementioned compounds of the generalformula (I) according to the invention is preferred.

The new active compounds can be converted in a known manner into thecustomary formulations, such as plain tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, non-toxic, pharmaceutically suitable excipients or solvents. Thetherapeutically active compound should be present here in each case in aconcentration of about 0.5 to 90% by weight of the total mixture, i.e.in amounts which are sufficient to achieve the stated dosage range.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or excipients, if appropriate usingemulsifying agents and/or dispersing agents, it being possible, forexample if water is used as the diluent, to use organic solvents asauxiliary solvents if appropriate.

The formulations are administered in the customary manner, preferablyorally or parenterally, in particular perlingually or intravenously.

In the case of parenteral use, solutions of the active compound can beemployed, using suitable liquid carrier materials.

In general, it has proved advantageous in the case of intravenousadministration to administer amounts of about 0.001 to 1 mg/kg,preferably about 0.01 to 0.5 mg/kg of body weight to achieve effectiveresults, and in the case of oral administration the dosage is about 0.01to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.

Nevertheless, it may be necessary to deviate from the amounts mentioned,and in particular as a function of the body weight or the nature of theadministration route, of the behaviour of the individual towards themedicament, the nature of the formulation thereof and the time orinterval at which administration takes place. Thus, in some cases it maybe sufficient to manage with less than the abovementioned minimumamount, while in other cases the upper limit mentioned must be exceeded.In the case where relatively large amounts are administered, it may beadvisable to divide these into several individual doses over the courseof the day.

Abbreviations used:

CI=Chemical Ionization

cHept=Cycloheptyl

cHex=CyclohexyL

cPent=Cyclopentyl

d=Doublet

DCCI=N'-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide

dd=Doublet doublets

dia=Diastereomer

DMF=N,N-Dimethylformamide

DMSO=Dimethyl sulphoxide

EI=Electron impact ionization

FAB=Fast Atom Bombardment

HOBT=1-Hydroxy-1H-benzotriazole

Hz=Hertz

iBu=Isobutyl

iPr=Isopropyl

m=Multiplet

Me=Methyl

nPr=Normal propyl

Ph=Phenyl

RT=Room temperature

s=Singlet

t=Triplet

TFA=Trifluoroacetic acid

THF=Tetrahydrofuran

TMS=Tetramethylsilane

    ______________________________________                                        Solvent mixtures used                                                         ______________________________________                                        Petroleum ether:acetone =                                                                             1:1    (A)                                            Petroleum ether:ethyl acetate =                                                                       20:1   (B)                                            Petroleum ether:ethyl acetate =                                                                       10:1   (C)                                            Petroleum ether:ethyl acetate =                                                                       5:1    (D)                                            Petroleum ether:ethyl acetate =                                                                       3:1    (E)                                            Petroleum ether:ethyl acetate =                                                                       4:1    (F)                                            Petroleum ether:ethyl acetate =                                                                       2:1    (G)                                            Petroleum ether:ethyl acetate =                                                                       1:1    (H)                                            Petroleum ether:ethyl acetate =                                                                       1:2    (I)                                            Methylene chloride:methanol =                                                                         50:1   (J)                                            Methylene chloride:methanol =                                                                         20:1   (K)                                            Methylene chloride:methanol =                                                                         10:1   (L)                                            Methylene chloride:ethyl acetate =                                                                    1:1    (M)                                            Methylene chloride:ethanol =                                                                          50:1   (N)                                            Methylene chloride (100%) =    (O)                                            Ethyl acetate:methanol =                                                                              10:1   (P)                                            Toluene (100%) =               (Q)                                            Toluene:ethyl acetate = 1:1    (R)                                            Toluene:ethyl acetate = 8:1    (S)                                            Toluene:ethyl acetate = 9:1    (T)                                            Cyclohexanol:ethyl acetate =                                                                          1:1    (U)                                            Cyclohexanol:ethyl acetate =                                                                          7:3    (V)                                            ______________________________________                                    

Additional information

If FAB has not been used, the following identifications apply in all theTables which follow:

*=EI

#=CI (NH₃)

EXAMPLE I Methyl 2-(R&S)-phenyl-2-(4-methyl)phenylacetate ##STR9##

21.0 g (100 mmol, apin) of 2-phenyl-1-(4-methyl)phenyl-1-oxoethane and38.8 g (120 mmol) of iodobenzenediacetate were dissolved in 300 ml oftrimethyl orthoformate. 19.6 g of concentrated sulphuric acid were addedto this solution and the solution was heated at 60° C. for 6 hours. Itwas cooled to room temperature, diluted with water (100 ml) andextracted with diethyl ether. The combined organic phases were driedover sodium sulphate and concentrated on a rotary evaporator. Theresidue was purified by column chromatography.

Yield 13.1 g (55%);

R_(f) =0.33 (petroleum ether:ethyl acetate, 20:1);

Mass (calculated) for C₁₆ H₁₆ O₂ =240.30; mass spectrum (FAB, relativeintensity) 241 (25%), 181 (100%);

¹ H NMR (200 MHz, CDCl₃) δ7.3-7.10 (m, 9H), 4.99 (s, 1H), 3.73 (s, 3H),2.31 (2, 3H).

EXAMPLE II tert-Butyl 2-cyclopentyl-2-(4-methylphenyl)-acetate ##STR10##

33.5 g (0.3 mol) of potassium tert-butylate are initially introducedinto 100 ml of anhydrous DMF at 0° C., and 51.6 g (0.25 mol) oftert-butyl 4-methylphenyl-acetate in 250 ml of anhydrous DMF are addeddropwise. The mixture is stirred at 0° C. for 30 minutes, 32.2 ml (0.3mol) of cyclopentyl bromide in 150 ml of anhydrous DMF are addeddropwise at 5°-15° C. and the mixture is stirred at 25° C. for 20 hours.After concentration, the residue is partitioned between water anddiethyl ether and the ether phase is dried over sodium sulphate andconcentrated. The product crystallizes out.

Yield: 67 g (97.5% of theory);

Melting point: 50°-53° C.

The compounds of Table I are prepared analogously to the instructions ofExample II:

                  TABLE I                                                         ______________________________________                                         ##STR11##                                                                    Example No. R.sup.1      R.sup.8  R.sub.f *                                   ______________________________________                                        III         (R&S) iPr    Me       0.86 (T)                                    IV          (R&S) iBu    tBu      0.84 (S)                                    V           (R&S) cPent  Me       0.59 (C)                                    VI          (R&S) cHex   Me       0.38 (B)                                    VII         (R&S) cHex   tBu      0.71 (Q)                                    VIII        (R&S) cHept  Me       0.57 (Q)                                    IX          (R&S) cHept  tBu      0.32 (Q)                                    ______________________________________                                    

EXAMPLE X tert-Butyl 2-(4-bromomethyl-phenyl)-2-cyclopentyl-acetate##STR12##

27.4 g (0.1 mol) of the compound from Example II are dissolved in 200 mlof carbon tetrachloride and the solution is heated to the boiling point.After addition of 0.82 g of azobisisobutyronitrile, 18.7 g (0.105 mol)of N-bromosuccinimide are added in portions, the mixture is thenrefluxed for 1 hour and cooled to 0° C. and the succinimide is filteredoff. After concentration of the filtrate, the product precipitates out.It is washed with petroleum ether (40/60) and dried.

Yield: 20 g (57% of theory);

Melting point: 73°-76° C.

The compounds of Table II are prepared analogously to the instructionsof Example X:

                  TABLE II                                                        ______________________________________                                         ##STR13##                                                                    Example No.                                                                           R.sup.1   R.sup.19                                                                              R.sub.f *                                                                             Starting compound                           ______________________________________                                        XI      (R&S) iPr Me      0.78 (O)                                                                              III                                         XII     (R&S) iBu tBu     0.86 (O)                                                                              IV                                          XIII    (R&S) cPent                                                                             Me      0.63 (C)                                                                              V                                           XIV     (R&S) cHex                                                                              Me      0.74 (O)                                                                              VI                                          XV      (R&S) cHex                                                                              tBu     0.58 (C)                                                                              VII                                         XVI     (R&S) cHept                                                                             tBu     0.84 (O)                                                                              VIII                                        XVII    (R&S) Ph  Me      0.74 (O)                                                                              IX                                          ______________________________________                                    

EXAMPLE XVIII 4-Carboethoxy-2-phenylthiazole ##STR14##

13.19 g (96 mmol) of thiobenzamide are dissolved in 260 ml of THF. Asolution of 25.0 g (115.37 mmol, 90% pure) of ethyl bromopiruvate in 250ml of THF is added dropwise at room temperature. During this operation,the temperature rises to 35° C. The mixture is boiled under refluxovernight and concentrated on a rotary evaporator and the residue isextracted with ethyl acetate and saturated NaHCO₃ solution. The organicphase is dried over sodium sulphate and concentrated on a rotaryevaporator. The residue is purified by column chromatography (silica gelMerck 60 (0.040-0.063)):

Yield: 20.1 g (89.6%);

R_(f) =0.66 (petroleum ether:ethyl acetate 3:1);

Mass (calculated) for C₁₂ H₁₁ NO₂ =233.29; mass spectrum (CI, relativeintensity) 234 (100%);

¹ H NMR (200 MHz, CDCl₃) δ8.15 (s, 1H), 8.03-7.99 (m, 2H), 7.48-7.42 (m,3H), 4.46 (q, J=7.11 Hz, 2H), 1.43 (t, J=7.16 Hz, 3H).

EXAMPLE XIX 4-Carboxy2-phenylthiazole ##STR15##

20.1 g (86.2 mmol) of the compound from Example XVII are dissolved in400 ml of ethanol. A solution of 17.2 g (430.8 mmol) of sodium hydroxidelozenges in 80 ml of water is added. The mixture is boiled under refluxfor 6 hours. Water is added and the pH is brought to 6 withhalf-concentrated hydrochloric acid, while cooling with ice. The mixtureis concentrated on a rotary evaporator and the residue is extracted withethyl acetate and water. The organic phase is dried over sodium sulphateand concentrated on a rotary evaporator.

Yield: 13.6 g (76.9%);

Melting point=170°-172° C.;

R_(f) =0.11 (CH₂ Cl₂ :methanol, 20:1);

Mass (calculated) for C₁₀ H₇ NO₂ S=205.24; mass spectrum (EI, relativeintensity) 205 (100%);

¹ H NMR (250 MHz, DMSO-D₆) δ13.2 (bs, 1H), 8.52 (s, 1H), 8.01-7.96 (m,2H), 7.60-7.45 (m, 3H).

EXAMPLE XX 2- 4-(2-Phenyl)thiazolyl!benzimidazole ##STR16##

13.3 g (64.8 mmol) of the compound from Example XIX and 7.0 g (64.8mmol) of diaminobenzene are mixed with one another. 70 ml ofpolyphosphoric acid are slowly added, while stirring constantly with anoverhead stirrer. The mixture is heated at 100° C. for 1 hour and at140° C. for 6 hours. Water and sodium hydroxide lozenges are added,while cooling with ice, and the pH is brought to 12. Ethyl acetate isadded and the mixture is extracted. The organic phase is dried oversodium sulphate and concentrated on a rotary evaporator. The residue istriturated with CH₂ Cl₂, filtered off with suction and dried.

Yield: 4.3 g (23.9%);

Melting point=183°-191° C.;

R_(f) =0.51 (petroleum ether:ethyl acetate, 1:1);

Mass (calculated) for C₁₆ H₁₁ N₃ S=277.35; mass spectrum (EI, relativeintensity) 277 (85%), 174 (100%);

¹ H NMR (250 MHz, DMSO-D₆) δ12.9 (bs, 1H), 8.44 (s, 1H), 8.16-8.09 (m,2H), 7.63-7.52 (m, 5H), 7.27-7.22 (2H).

The compounds listed in Table III were prepared analogously to theinstructions of Example XX:

                                      TABLE III                                   __________________________________________________________________________    Example                   Yield  R.sub.f                                                                            Melting point                                                                        MS (El)                          No.  A                    (% of theory)                                                                        (solvent)                                                                          (°C.)                                                                         (relative intensity)             __________________________________________________________________________    XXI                                                                                 ##STR17##           23     0.52 (K)                                                                           184-86 278 (60%) , 277 (55%), 276                                                    (100%), 175 (95%)                XXII                                                                                ##STR18##           22     0.72 (R)                                                                           216-24 250 (100%)                       XXIII                                                                               ##STR19##           23     0.80 (P)                                                                             165  200 (20%),  111 (100%)           XXIV                                                                                ##STR20##           60     0.47 (P)                                                                           204-10 195 (100%)                       XXV                                                                                 ##STR21##           36     0.39 (P)                                                                           >240   195 (100%)                       XXVI                                                                                ##STR22##           33     0.40 (P)                                                                           182-84 208 (95%),  207 (100%)           XXVII                                                                               ##STR23##           19     0.45 (P)                                                                           >220   200 (100%)                       __________________________________________________________________________

EXAMPLE XXVI tert-Butyl 2-cyclopentyl-2-4-(2-methyl-4-oxo-4H-quinazolin-3-yl-methyl)phenyl!acetat ##STR24##

374 mg (9.34 mmol) of sodium hydride (60% pure in paraffin) areinitially introduced into 1.0 ml of DMF. The mixture is cooled to 0° C.and a solution of 1.50 g (9.34 mmol) of 2-methyl-4(3H)-quinazolinone in15 ml of DMF is slowly added dropwise. The mixture is subsequentlystirred for half an hour, during which the temperature rises to 20° C.The mixture is cooled again, 3.0 g (8.49 mmol) of the compound fromExample II are dissolved in 20 ml of DMF, and this solution is addeddropwise. The mixture is stirred overnight at room temperature. Water ispoured in and the mixture is extracted (3 times) with ether. Thecombined organic phases are dried over sodium sulphate and concentratedon a rotary evaporator. The residue is purified by column chromatography(silica gel Merck 60 (0.040-0.063)):

Yield: 2.88 g (78.3%);

Melting point=128° C.;

R_(f) =0.54 (CH₂ Cl₂ :methanol, 100:5);

Mass (calculated) for C₂₇ H₃₂ N₂ O₃ =432.567; mass spectrum (FAB,relative intensity) 433 (100%), 377 (100%), 376 (40%);

¹ H NMR (250 MHz, CDCl₃) δ8.31 (dd, J=7.59 Hz, J=1.25 Hz, 1H), 7.77 (m,1H), 7.63 (d, J=8.0 Hz, 1H), 7.47 (m, 1H), 7.28 (d, J=8.22 Hz, 2H), 7.14(d, J=8.26 Hz, 2H), 5.37 (s, 2H), 3.12 (d, J=11.06 Hz, 1H), 2.54 (s,3H), 2.47 (m, 1H), 1.90 (m, 1H), 1.65 -1.10 (m, 6H), 1.38 (s, 9H), 0.92(m, 1H);

¹³ C NMR (50 MHz, CDCl₃) δ173.02 (s), 162.41 (s), 154.63 (s), 147.36(s), 139.16 (s), 134.40 (d), 134.37 (s), 128.74 (d), 127.12 (d), 126.72(d), 126.59 (d), 126.51 (d), 120.39 (s), 80.55 (s), 58.60 (d), 46.89(t), 43.67 (d), 31.24 (t), 30.77 (t), 27.96 (q), 25.13 (t), 24.82 (t),23.48 (q).

The compounds listed in Table IV are prepared analogously to theinstructions of Example XXVIII:

                                      TABLE IV                                    __________________________________________________________________________     ##STR25##                                                                    Table                               Yield  R.sub.f                                                                            Melting                                                                              MSint                  No.  A                    R.sup.1                                                                             R.sup.15                                                                          (% of theory)                                                                        (solvent)                                                                          (°C.)                                                                         (relative                                                                     intensity)             __________________________________________________________________________    XXIX                                                                                ##STR26##           (R&S) cPent                                                                         Me  100    0.33 (J)     395 (100%)            XXX                                                                                 ##STR27##           (R&S) cHept                                                                         tBu 78     0.32 (J)                                                                           101    *464 (100%)            XXXI                                                                                ##STR28##           (R&S) cPent                                                                         Me  28     0.54 (J) 0.33                                                                      121     423 (100%)            XXXII                                                                               ##STR29##           (R&S) cPent                                                                         Me  54     0.34 (J)     409 (100%),  163                                                             (40%)                  XXXIII                                                                              ##STR30##           (R&S) cPent                                                                         Me  61     0.39 (J)     420 (100%)            XXXIV                                                                               ##STR31##           (R&S) cPent                                                                         Me  68     0.54 (J)     471 (100%),  91                                                              (55%)                  XXXV                                                                                ##STR32##           (R&S) cPent                                                                         Me  68     0.37 (D) 0.10                                                                      60 (foam)                                                                             541 (50%),  539                                                              (80%),  163                                                                   (100%)                 XXXVI                                                                               ##STR33##           (R&S) cPent                                                                         Me  66     0.60 (J)     499 (100%)            XXXVII                                                                              ##STR34##           (R&S) cPent                                                                         tBu 48     0.26 (E)                                                                           136-27  481 (100%)            XXXVIII                                                                             ##STR35##           (R&S) cPent                                                                         tBu 57     0.59 (J)                                                                           154     57 (38%)              XXXIX                                                                               ##STR36##           (R&S) cPent                                                                         tBu 58     0.82 (K)                                                                           132     549 (75%),  57                                                               (100%)                 XL                                                                                  ##STR37##           (R&S) cPent                                                                         tBu 62     0.22 (J)                                                                           165     474 (100%)            XLI                                                                                 ##STR38##           (R&S) cHex                                                                          Me  97     0.23 (J)                                                                            65     446 (100%),  163                                                             (40%)                  XLII                                                                                ##STR39##           (R&S) cHept                                                                         tBu 86     0.24 (J)                                                                           169    *501 (100%),  57                                                              (100%)                 XLIII                                                                               ##STR40##           (R&S) cPent                                                                         tBu 70     0.31 (K)                                                                           168-70  488 (100%)            XLIV                                                                                ##STR41##           (R&S) cPent                                                                         tBu 62     0.48 (J)                                                                           192     550 (100%)            XLV                                                                                 ##STR42##           (R&S) cPent                                                                         tBu 19     0.26 (J)                                                                           164     473 (100%),  57                                                              (35%)                  XLVI                                                                                ##STR43##           (R&S) cPent                                                                         tBu 51     0.41 (J)                                                                           188     501 (100%)            XLVII                                                                               ##STR44##           (R&S) cPent                                                                         tBu 98     0.40 (E)                                                                           154-59  473 (100%)            XLVIII                                                                              ##STR45##           (R&S) cPent                                                                         tBu 62     0.70 (J)                                                                           186     501 (100%)            XLIX                                                                                ##STR46##           (R&S) cPent                                                                         tBu 51     0.60 (E) 0.67                                                                      188     523 (100%)                  ##STR47##           (R&S) cPent                                                                         tBu 68     0.45 (J)                                                                           152     468 (100%)            LI                                                                                  ##STR48##           (R&S) cHept                                                                         tBu 91     0.28 (G)                                                                           147    *495 (100%),  57                                                              (100%)                 LII                                                                                 ##STR49##           (R&S) cPent                                                                         tBu 59     0.32 (K)                                                                           107     468 (100%),  57                                                              (100%)                 LIII                                                                                ##STR50##           (R&S) cPent                                                                         tBu 45     0.31 (K)                                                                            98     468 (100%),  57                                                              (100%)                 LIV                                                                                 ##STR51##           (R&S) cHept                                                                         tBu 65     0.41 (O)                                                                           145    *435 (100%),  57                                                              (100%)                 LV                                                                                  ##STR52##           (R&S) cPent                                                                         tBu 53     0.69 (J)                                                                            78     451 (100%),  57                                                              (70%)                  LVI                                                                                 ##STR53##           (R&S) cHept                                                                         tBu 100    0.31 (D)                                                                            91     451 (70%),  395                                                              (100%)                 LVII                                                                                ##STR54##           (R&S) cHept                                                                         tBu 91     0.54 (D)                                                                           133     465 (60%),  410                                                              (100%)                 LVIII                                                                               ##STR55##           (R&S) cHept                                                                         tBu 76     0.53 (O)                                                                           158     446 (50%),  57                                                               (100%)                 LIX                                                                                 ##STR56##           (R&S) cHept                                                                         tBu 81     0.24 (J)                                                                           133     449 (40%),  57                                                               (100%)                 LX                                                                                  ##STR57##           (R&S) cHept                                                                         tBu 70     0.48 (O)                                                                           114                           LXI                                                                                 ##STR58##           (R&S) cPent                                                                         tBu 29     0.46 (E)                                                                           oil     447 (60%),  57                                                               (100%)                 LXII                                                                                ##STR59##           (R&S) cHept                                                                         tBu 56     0.36 (E)                                                                           151     447 (55%),  391                                                              (100%)                 LXIII                                                                               ##STR60##           (R&S) cPent                                                                         tBu 74     0.84 (K)                                                                           oil     475 (40%),  419                                                              (100%)                 LXIV                                                                                ##STR61##           (R&S) cPent                                                                         tBu 93     0.90 (K)                                                                           oil     529 (40%),  473                                                              (100%)                 __________________________________________________________________________

EXAMPLE LXV Cyclopentyl-4-(4-methyl-2-thioxo-2,3-dihydro-benzoimidazol-1-ylmethyl)phenyl!aceticacid ##STR62##

1.93 g (4.29 mmol) of the compound from Example LV are dissolved in 20ml of dioxane, and 1 ml of concentrated hydrochloric acid is added tothe solution. The mixture is boiled under reflux overnight and cooled,and 25 ml of cold water are added. The precipitate formed is filteredoff with suction and dried.

Yield: 1.28 g (78.6%);

Melting point=>225° C.;

R_(f) =0.35 (CH₂ Cl₂ :methanol, 100:5);

Mass (calculated) for C₂₂ H₂₄ N₂ O₂ S=380.51

EXAMPLE LXVI Cycloheptyl-4-(2-thioxo-2,3-dihydro-benzoimidazol-1-ylmethyl)phenyl!acetic acid##STR63##

The reaction is carried out with 1.30 g of the compound from Example XXXanalogously to the instructions of Example LXV.

Yield: 162 mg (15%);

Melting point=245° C.;

R_(f) =0.73 (petroleum ether:ethyl acetate, 2:1).

EXAMPLE LXVII 2-Cyclopentyl-2-4-(2-methyl-4-oxo-4H-quinazolin-3-yl-methyl)phenyl!acetic acid ##STR64##

2.8 g (6.47 mmol) of the compound from Example XXXVII are dissolved in25 ml of dioxane. 1.4 ml of concentrated hydrochloric acid are added andthe mixture is boiled under reflux overnight. Water and CH₂ Cl₂ areadded and the mixture is extracted. The organic phase is dried oversodium sulphate and concentrated on a rotary evaporator. The residue ispurified by column chromatography (silica gel Merck 60 (0.040-0.063)):

Yield: 1.68 g (68.9%);

Melting point=181° C. (foam);

R_(f) =0.39 (CH₂ Cl₂ :methanol 100:5);

Mass (calculated) for C₂₃ H₂₄ N₂ O₃ =376.459: mass spectrum (FAB,relative intensity) 378 (40%), 377 (100%);

¹ H NMR (200 MHz, CDCl₃) δ8.31 (dd, J=7.74 Hz, J=1.06 Hz, 1H), 7.80-7.62(m, 2H), 7.45 (m, 1H), 7.29 (d, J=8.24 Hz, 2H), 7.12 (d, J=8.17 Hz, 2H),5.36 (s, 2H), 3.26 (d, J=11.12 Hz, 1H), 2.51 (m, 1H), 2.50 (s, 3H), 1.95(m, 1H), 1.70-1.20 (m, 6H), 0.97 (m, 1H).

The compounds listed in Table V are prepared analogously to theinstructions of Examples LXV-LXVII:

                                      TABLE V                                     __________________________________________________________________________     ##STR65##                                                                                                                            Starting                                             Yield (% of Melting point                                                                        MS (relative                                                                        material              Example No.                                                                         A                  R.sup.1                                                                             theory)                                                                             R.sub.r (solvent)                                                                   (°C.)                                                                         intensity)                                                                          (Example              __________________________________________________________________________                                                            No.)                  LXVIII                                                                               ##STR66##         (R&S) cPent                                                                         68    0.22 (K)                                                                            198    381 (100%)                                                                          XXVII                 LXIX                                                                                 ##STR67##         (R&S) cHept                                                                         41    0.50 (I)                                                                            229    #409 (100%)                                                                         XXVIII                LXX                                                                                  ##STR68##         (R&S) cPent                                                                         64    0.19 (K)                                                                            208    409 (100%), 154                                                                     XXIX)                 LXXI                                                                                 ##STR69##         (R&S) cPent                                                                         77    0.30 (K)                                                                            180    395 (100%), 277                                                                     XXX%)                 LXXII                                                                                ##STR70##         (R&S) cPent                                                                         76    0.28 (K)                                                                            159    407 (100%), 367 (45%)       LXXIII                                                                               ##STR71##         (R&S) cPent                                                                         80    0.44 (K)                                                                            165    457 (100%)                  LXXIV                                                                                ##STR72##         (R&S) cPent                                                                         48    0.44 (K)                                                                            104 (foam)                                                                           527 (65%), 525 (100%)       LXXV                                                                                 ##STR73##         (R&S) cPent                                                                         18    0.37 (K)                                                                            96 (foam)                                                                            485 (100%)                  LXXVI                                                                                ##STR74##         (R&S) cPent                                                                         58    0.35 (L)                                                                            215-17 425 (100%)                  LXXVII                                                                               ##STR75##         (R&S) cPent                                                                         100   0.33 (K)                                                                            >225   493 (100%), 307 (50%)       LXXVIII                                                                              ##STR76##         (R&S) cPent                                                                         36    0.33 (K)                                                                            212    431 (100%)                  LXXIX                                                                                ##STR77##         (R&S) cPent                                                                         100   0.25 (K)                                                                            >210   418 (100%)                  LXXX                                                                                 ##STR78##         (R&S) cHex                                                                          57    0.21 (K)                                                                            232    432 (100%)                  LXXXI                                                                                ##STR79##         (R&S) cHept                                                                         90    0.13 (K) 0.55 (L)                                                                   >204   #446 (100%)                 LXXXII                                                                               ##STR80##         (R&S) cPent                                                                         72    0.33 (L)                                                                            >240   432 (100%), 154 (60%)       LXXXIII                                                                              ##STR81##         (R&S) cPent                                                                         91    0.30 (K)                                                                            163    494 (100%), 154                                                                     XLII)                 LXXXIV                                                                               ##STR82##         (R&S) cPent                                                                         89    0.07 (K) 0.69 (L)                                                                   >220   417 (100%)                                                                          XLIII                 LXXXV                                                                                ##STR83##         (R&S) cPent                                                                         93    0.44 (K)                                                                            >238   445 (100%)                                                                          XLIL                  LXXXVI                                                                               ##STR84##         (R&S) cPent                                                                         41    0.36 (L)                                                                            223-25 417 (100%)                                                                          XLV                   LXXXVII                                                                              ##STR85##         (R&S) cPent                                                                         94    0.30 (K)                                                                            >210         XLVIII                LXXXVIII                                                                             ##STR86##         (R&S) cPent                                                                         85    0.27 (K)                                                                            111-15 (foam)                                                                        467 (100%), 154                                                                     XLIX)                 LXXXIX                                                                               ##STR87##         (R&S) cPent                                                                         67    0.57 (L)                                                                            >230   *411  (100%), 342                                                                   L90%)                 XC                                                                                   ##STR88##         (R&S) cHept                                                                         100   0.22 (K)                                                                            118 (foam)                                                                           *439 (90%), 342                                                                     LI00%)                XCI                                                                                  ##STR89##         (R&S) cPent                                                                         64    0.59 (K)                                                                            121 (foam)                                                                           412 (100%)                                                                          LII                   XCII                                                                                 ##STR90##         (R&S) cPent                                                                         94    0.37 (L)                                                                            202    412 (100%), 307                                                                     LIII%)                XCIII                                                                                ##STR91##         (R&S) cHept                                                                         86    0.31 (K) 0.37 (H)                                                                   212    #397 (100%), 334                                                                    LIV0%)                XCIV                                                                                 ##STR92##         (R&S) cHept                                                                         93    0.45 (K)     *394 (30%), 57                                                                      LVI0%)                XCV                                                                                  ##STR93##         (R&S) cHept                                                                         69    0.44 (K)                                                                            78 (foam)                                                                            *409 (50%), 165                                                                     LVII%)                XCVI                                                                                 ##STR94##         (R&S) cHept                                                                         88    0.36 (K)                                                                            193    *391 (20%), 295                                                                     LVIII)                XCVII                                                                                ##STR95##         (R&S) cHept                                                                         48    0.14 (K)                                                                            107 (foam)                                                                           393 (100%)                                                                          LIX                   XCVIII                                                                               ##STR96##         (R&S) cHept                                                                         90    0.38 (K)                                                                            154          LX                    XCIX                                                                                 ##STR97##         (R&S) cPent                                                                         87    0.28 (K)     391 (100%)                                                                          LXI                          ##STR98##         (R&S) cHept                                                                         84    0.33 (K)                                                                            176    *390 (60%), 148                                                                     LXII%)                CI                                                                                   ##STR99##         (R&S) cPent                                                                         100   0.30 (K)     419 (100%)                                                                          LXIII                 CII                                                                                  ##STR100##        (R&S) cPent                                                                         69    0.30 (K)                                                                            213-15 473 (40%), 353                                                                      LXIV%)                __________________________________________________________________________

PREPARATION EXAMPLES EXAMPLE 12-Cyclopentyl-N-(2-hydroxy-1-(R)-phenylethyl)-2-4-(2-methyl-4-oxy-4H-quinazolin-3-yl-methyl)phenyl!acetamide ##STR101##

1.645 g (4.37 mmol) of the compound from Example LXVII are dissolved in20 ml of CH₂ Cl₂. 599 mg (4.37 mmol) of R-phenylglycinol, 649 mg (4.81mmol) of 1-hydroxy-benzotriazole, 963 mg (5.02 mol) ofN'-(3dimethylaminopropyl)-N-ethylcarbodiimide×HCl and 884 mg (8.74 mmol)of triethylamine are added in succession. The mixture is subsequentlystirred overnight at room temperature. The solution is diluted with 20ml of CH₂ Cl₂ and extracted with saturated NH₄ Cl solution and saturatedNaHCO₃ solution. The organic phase is dried over sodium sulphate andconcentrated on a rotary evaporator. The residue is purified by columnchromatography (silica gel Merck 60 (0.040-0.063):

Yield: 1.11 g(51.0%);

Melting point=97° C. (foam);

R_(f) =0.50 (CH₂ Cl₂ :methanol, 100:5);

Mass (calculated) for C₃₁ H₃₃ N₃ O₃ =495.627, mass spectrum (FAB,relative intensity) 496 (100%), 307 (40%).

The compounds listed in Table 1 are prepared analogously to theinstructions of Example 1:

    TABLE 1                                                                          -                                                                              ##STR102##                                                                            Starting                                                                    Yield (% of  Melting point MS (relative material                           Example No. A R.sup.1 Y theory) R.sub.r                                        (solvent) (°C.) intensity) (Example No.)                                2                                                                              ##STR103##                                                                     (R&S)cPent                                                                     ##STR104##                                                                     95 0.11 (K) 83(foam) 500 (100%) LXIX                                          3                                                                               ##STR105##                                                                     (dia A)cPent                                                                   ##STR106##                                                                       195-96  2                                                                   4                                                                               ##STR107##                                                                     (dia B)cPent                                                                   ##STR108##                                                                       215-16  2                                                                   5                                                                               ##STR109##                                                                     (R&S)cHept                                                                     ##STR110##                                                                     69 0.41 (K) 175-77 528 (100%) LXIX                                            6                                                                               ##STR111##                                                                     (dia A)cPent                                                                   ##STR112##                                                                       213  5                                                                      7                                                                               ##STR113##                                                                     (dia B)cHept                                                                   ##STR114##                                                                       188  5                                                                      8                                                                               ##STR115##                                                                     (R&S)cPent                                                                     ##STR116##                                                                     74 0.17 (K) 107foam 528 (100%) LXX                                            9                                                                               ##STR117##                                                                     (R&S)cPent                                                                     ##STR118##                                                                     60 0.39 (K) 87foam 514 (100%) LXXI                                            10                                                                              ##STR119##                                                                     (R&S)cPent                                                                     ##STR120##                                                                     69 0.40 (K) 83foam 526 (100%) LXXII                                           11                                                                              ##STR121##                                                                     (R&S)cPent                                                                     ##STR122##                                                                     52  90foam 576 (100%) LXXIII                                                  12                                                                              ##STR123##                                                                     (dia A)cPent                                                                   ##STR124##                                                                      0.39 (K)   II                                                                13                                                                              ##STR125##                                                                     (dia B)cPent                                                                   ##STR126##                                                                      0.32 (K)   II                                                                14                                                                              ##STR127##                                                                     (R&S)cPent                                                                     ##STR128##                                                                     85   644 (100%),171 (50%) LXXIV                                               15                                                                              ##STR129##                                                                     (dia A)cPent                                                                   ##STR130##                                                                      0.44 (K) 217  14                                                             16                                                                              ##STR131##                                                                     (dia B)cPent                                                                   ##STR132##                                                                      0.35 (K) 115  14                                                             17                                                                              ##STR133##                                                                     (R&S)cPent                                                                     ##STR134##                                                                     39  90 604 (100%) LXXV                                                        18                                                                              ##STR135##                                                                     (dia A)cPent                                                                   ##STR136##                                                                      0.44 (K)   17                                                                19                                                                              ##STR137##                                                                     (dia B)cPent                                                                   ##STR138##                                                                      0.35 (K)   17                                                                20                                                                              ##STR139##                                                                     (R&S)cPent                                                                     ##STR140##                                                                     64 0.39 (K) (foam) 544 (100%) LXXVI                                           21                                                                              ##STR141##                                                                     (R&S)cPent                                                                     ##STR142##                                                                     91 0.40 (K) 98(foam) 614 (75%),612 (100%) LXXVII                              22                                                                              ##STR143##                                                                     (R&S)cPent                                                                     ##STR144##                                                                     85 0.28 (K) 92(foam) 550 (100%),105 (65%) LXXVIII                             23                                                                              ##STR145##                                                                     (dia A)cPent                                                                   ##STR146##                                                                       178  22                                                                     24                                                                              ##STR147##                                                                     (dia B)cPent                                                                   ##STR148##                                                                       204  22                                                                     25                                                                              ##STR149##                                                                     (R&S)cPent                                                                     ##STR150##                                                                     62 0.28 (K) 104(foam) 537 (100%) LXXIX                                        26                                                                              ##STR151##                                                                     (dia A)cPent                                                                   ##STR152##                                                                       208-09  25                                                                  27                                                                              ##STR153##                                                                     (dia B)cPent                                                                   ##STR154##                                                                       199-201  25                                                                 28                                                                              ##STR155##                                                                     (R&S)cHex                                                                      ##STR156##                                                                     81 0.38 (K) 122(foam) 551 (100%),154 (40%) LXXX                               29                                                                              ##STR157##                                                                     (R&S)cHept                                                                     ##STR158##                                                                     77 0.27 (K) 213 565 (100%) LXXXI                                              30                                                                              ##STR159##                                                                     (dia A)cHept                                                                   ##STR160##                                                                       >230  29                                                                    31                                                                              ##STR161##                                                                     (dia B)cHept                                                                   ##STR162##                                                                       177  29                                                                     32                                                                              ##STR163##                                                                     (R&S)cHept                                                                     ##STR164##                                                                     75 0.37 (K) 182 535 (100%) LXXXI                                              33                                                                              ##STR165##                                                                     (R&S)cPent                                                                     ##STR166##                                                                     78 0.18 (K) 104(foam) 551 (100%) LXXXII                                       34                                                                              ##STR167##                                                                     (dia A)cPent                                                                   ##STR168##                                                                       108(foam)  33                                                               35                                                                              ##STR169##                                                                     (dia B)cPent                                                                   ##STR170##                                                                       108(foam)  33                                                               36                                                                              ##STR171##                                                                     (R&S)cPent                                                                     ##STR172##                                                                     63 0.33 (K) 227 613 (100%),154 (75%) LXXX.I1I                                 37                                                                              ##STR173##                                                                     (R&S)cPent                                                                     ##STR174##                                                                     83 0.50 (L) 103(foam) 535 (100%),307 (42%) LXXXIV                             38                                                                              ##STR175##                                                                     (R&S)cPent                                                                     ##STR176##                                                                     57 0.44 (K) 131 564 (100%) LXXXV                                              39                                                                              ##STR177##                                                                     (R&S)cPent                                                                     ##STR178##                                                                     61 0.43 (K) (foam) 536 (100%) LXXXVI                                          40                                                                              ##STR179##                                                                     (R&S)cPent                                                                     ##STR180##                                                                     52 0.30 (K) 110 564 (100%) LXXXVII                                            41                                                                              ##STR181##                                                                     (R&S)cPent                                                                     ##STR182##                                                                     59  120-22(foam) 586 (100%) LXXXVIII                                          42                                                                              ##STR183##                                                                     (dia A)cHept                                                                   ##STR184##                                                                      0.35 (K)   41                                                                43                                                                              ##STR185##                                                                     (dia B)cHept                                                                   ##STR186##                                                                      0.31 (K)   41                                                                44                                                                              ##STR187##                                                                     (R&S)cPent                                                                     ##STR188##                                                                     97 0.43 (K) 103(foam) 531 (100%) LXXXIX                                       45                                                                              ##STR189##                                                                     (R&S)cHept                                                                     ##STR190##                                                                     77 0.34 (K) 107(foam) #559 (100%) XC                                          46                                                                              ##STR191##                                                                     (dia A)cHept                                                                   ##STR192##                                                                       >225  45                                                                    47                                                                              ##STR193##                                                                     (dia B)cHept                                                                   ##STR194##                                                                       188  45                                                                     48                                                                              ##STR195##                                                                     (R&S)cHept                                                                     ##STR196##                                                                     64 0.36 (K) 177 529 (100%) XC                                                 49                                                                              ##STR197##                                                                     (R&S)cPent                                                                     ##STR198##                                                                     85 0.45 (L) 104(foam) 531 (70%),154 (100%) XCI                                50                                                                              ##STR199##                                                                     (R&S)cPent                                                                     ##STR200##                                                                     79 0.47 (L) 109(foam) 531 (100%),307 (100%) XCII                              51                                                                              ##STR201##                                                                     (R&S)cHept                                                                     ##STR202##                                                                     75 0.45 (K) 161(foam) 499 (100%) XCIII                                        52                                                                              ##STR203##                                                                     (R&S)cHept                                                                     ##STR204##                                                                     76 0.31 (K) 136(foam) 514 (100%) LXV                                          53                                                                              ##STR205##                                                                     (R&S)cPent                                                                     ##STR206##                                                                     32 0.31 (K)  500 (100%),307 (40%) LXIV                                        54                                                                              ##STR207##                                                                     (dia A)cPent                                                                   ##STR208##                                                                       240  53                                                                     55                                                                              ##STR209##                                                                     (dia B)cPent                                                                   ##STR210##                                                                       257  53                                                                     56                                                                              ##STR211##                                                                     (R&S)cHept                                                                     ##STR212##                                                                     85 0.33 (K) 110 514 (100%) XCIV                                               57                                                                              ##STR213##                                                                     (dia A)cHept                                                                   ##STR214##                                                                       92  56                                                                      58                                                                              ##STR215##                                                                     (dia B)cHept                                                                   ##STR216##                                                                       175  56                                                                     59                                                                              ##STR217##                                                                     (R&S)cHept                                                                     ##STR218##                                                                     91 0.31 (K) 151 529 (100%) XCV                                                60                                                                              ##STR219##                                                                     (R&S)cHept                                                                     ##STR220##                                                                     88  143 511 (60%),77 (100%) XCVI                                              61                                                                              ##STR221##                                                                     (dia A)cHept                                                                   ##STR222##                                                                      0.43 (K)   60                                                                62                                                                              ##STR223##                                                                     (dia B)cHept                                                                   ##STR224##                                                                      0.26 (K)   60                                                                63                                                                              ##STR225##                                                                     (R&S)cHept                                                                     ##STR226##                                                                     68 0.39 (K) 97(foam) 512 (100%) XCVII                                         64                                                                              ##STR227##                                                                     (R&S)cHept                                                                     ##STR228##                                                                     48 0.46 (K) 157 547 (100%),199 (100%) XCVIII                                  65                                                                              ##STR229##                                                                     (dia A)cPent                                                                   ##STR230##                                                                       208  1                                                                      66                                                                              ##STR231##                                                                     (dia B)cPent                                                                   ##STR232##                                                                       228  1                                                                      67                                                                              ##STR233##                                                                     (R&S)cPent                                                                     ##STR234##                                                                     46 0.31 (K)  #527 (M +                                                         NH.sub.4,80%),510 (100%) XCIX                                                                        68                                                       ##STR235##                                                                     (dia A)cPent                                                                   ##STR236##                                                                       177-79  67                                                                  69                                                                              ##STR237##                                                                     (dia B)cPent                                                                   ##STR238##                                                                       180-183  67                                                                 70                                                                              ##STR239##                                                                     (R&S)cHept                                                                     ##STR240##                                                                     90  96(foam) 510 (100%) C                                                     71                                                                              ##STR241##                                                                     (dia A)cPent                                                                   ##STR242##                                                                      0.33 (K)   70                                                                72                                                                              ##STR243##                                                                     (dia B)cPent                                                                   ##STR244##                                                                      0.30 (K)   70                                                                73                                                                              ##STR245##                                                                     (R&S)cPent                                                                     ##STR246##                                                                     63 0.25(H)  538 (100%) CI                                                     74                                                                              ##STR247##                                                                     (dia A)cPent                                                                   ##STR248##                                                                       (foam)  73                                                                  75                                                                              ##STR249##                                                                     (dia B)cPent                                                                   ##STR250##                                                                       161-64  73                                                                  76                                                                              ##STR251##                                                                     (R&S)cPent                                                                     ##STR252##                                                                     69 0.33 (K)  592 (100%) CII                                                   77                                                                              ##STR253##                                                                     (dia A)cPent                                                                   ##STR254##                                                                       (foam)  76                                                                  78                                                                              ##STR255##                                                                     (dia B)cPent                                                                   ##STR256##                                                                       (foam)  76                                                             

EXAMPLE 79 2-(R/S)-Cycloheptyl-N-(2-hydroxy-1-(R)-phenylethyl)-2-4-(2-methyl-(R/S)-sulphinyl-benzimidazol-1-ylmethyl)phenyl!acetamide##STR257##

0.30 g (0.568 mmol) of the compound from Example 6 is dissolved in 10 mlof CH₂ Cl₂ and the solution is cooled to 0° C. 0.178 g (5.68 mmol, 55%pure) of m-chloroperbenzoic acid is slowly added. The mixture issubsequently stirred at 0° C. for 30 minutes and then at roomtemperature. After 1 hour, a little CH₂ Cl₂ and saturated NaHCO₃solution are added and the mixture is extracted. The organic phase isdried over sodium sulphate, concentrated on a rotary evaporator andpurified by column chromatography. (Silica gel Merck 60 (0.040-0.063)):

Yield: 33 mg (10.7%);

Melting point=158° C.;

R_(f) =0.25 (CH₂ Cl₂ :methanol, 100:5);

Mass (calculated) for C₃₂ H₃₇ N₃ O₃ S=543.74;

Mass spectrum (FAB, relative intensity) 444 (25%), 154 (80%), 55 (100%).

We claim:
 1. A bicyclic heterocyclic compound of the formula (I)##STR258## which A represents a radical of the formula ##STR259##wherein L and M are identical or different and denote hydrogen, halogen,trifluoromethyl, carboxyl, cycloalkyl having 3 to 6 carbon atoms,hydroxyl, phenyl or straight-chain or branched alkyl, alkoxycarbonyl oralkoxy having in each case up to 6 carbon atoms,R⁵ denotes hydrogen,straight-chain or branched alkyl having up to 6 carbon atoms, benzyl orphenyl, which are optionally substituted by halogen or by straight-chainor branched alkyl having up to 6 atoms, D and E are identical ordifferent and represent hydrogen, halogen, trifluoromethyl, hydroxyl orcarboxyl, or represent straight-chain or branched alkyl, alkoxy oralkoxycarbonyl having in each case up to 6 carbon atoms, Z represents anoxygen or sulphur atom, R.sup. represents cycloalkyl having 3 to 10carbon atoms, or represents straight-chain or branched alkyl having 1 to10 carbon atoms, or representsphenyl, which is optionally substituted upto twice in an identical or different manner by halogen, nitro, cyano,hydroxyl or straight-chain or branched alkyl or alkoxy having in eachcase up to 4 carbon atoms, R² represents hydrogen or straight-chain orbranched alkyl having up to 3 carbon atoms, R³ represents hydrogen orstraight-chain or branched alkyl having up to 5 carbon atoms, orrepresentscycloalkyl having 3 to 7 carbon atoms, or represents phenyl orbenzyl, or represents a 5- to 7-membered aromatic heterocyclic radicalhaving up to 3 heteroatoms selected from the groupconsisting of S, N andO, which are optionally substituted up to 3 times in an identical ordifferent manner by halogen, nitro, phenyl, hydroxyl or bystraight-chain or branched alkyl or alkoxy having up to 6 carbon atoms,R⁴ represents hydrogen, or represents a group of the formula

    --CH.sub.2 --OH or CH.sub.2 O--CO--R.sup.11,

wherein R¹¹ denotes hydrogen, straight-chain or branched alkyl having upto 8 carbon atoms or phenyl, which is optionally substituted up to 3times in an identical or different manner by halogen, hydroxyl, cyano orstraight-chain or branched alkyl or alkoxy having in each case up to 4carbon atoms,or a salt thereof.
 2. A bicyclic heterocyclic compound ofthe formula (I) according to claim 1, in whichA represents a radical ofthe formula ##STR260## wherein L and M are identical or different anddenotehydrogen, fluorine, chlorine, bromine, trifluoromethyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyl, phenyl orstraight-chain or branched alkyl, alkoxycarbonyl or alkoxy having ineach case up to 5 carbon atoms, R⁵ denotes hydrogen, straight-chain orbranched alkyl having up to 5 carbon atoms, benzyl or phenyl, which areoptionally substituted by fluorine, chlorine, bromine or bystraight-chain or branched alkyl having up to 5 carbon atoms, D and Eare identical or different and representhydrogen, fluorine, chlorine,bromine, trifluoromethyl, hydroxyl or straight-chain or branched alkylor alkoxy having in each case up to 4 carbon atoms, Z represents anoxygen or sulphur atom, R¹ represents cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl, or represents straight-chain orbranched alkyl having up to 7 carbon atoms, or representsphenyl, whichis optionally substituted by fluorine, chlorine, bromine, nitro, cyano,hydroxyl or straight-chain or branched alkyl or alkoxy having in eachcase up to 3 carbon atoms, R² denotes hydrogen or methyl, R³ representshydrogen or straight-chain or branched alkyl having up to 4 carbonatoms, benzyl, cyclopropyl, cyclopentyl or cyclohexyl, or representsphenyl, pyridyl, thienyl or furyl, which are optionally substituted upto twice in an identical or different manner by fluorine, chlorine,bromine, phenyl, nitro, hydroxyl or by straight-chain or branched alkylor alkoxy having up to 4 carbon atoms, R⁴ represents hydrogen, orrepresents a group of the formula --CH₂ --OH or --CH₂ O--CO--R¹¹,whereinR¹¹ denotes hydrogen, straight-chain or branched alkyl having up to 6carbon atoms or phenyl, which is optionally substituted up to twice inan identical or different manner by fluorine, chlorine, bromine, cyano,hydroxyl or straight-chain or branched alkyl or alkoxy having in eachcase up to 3 carbon atoms,or a salt thereof.
 3. A bicyclic heterocycliccompound of the formula according to claim 1, in whichA represents aradical of the formula ##STR261## wherein L and M are identical ordifferent and denotehydrogen, fluorine, chlorine, bromine, hydroxyl,phenyl or straight-chain or branched alkyl or alkoxy having in each caseup to 4 carbon atoms, R⁵ denotes hydrogen, straight-chain or branchedalkyl having up to 4 carbon atoms, benzyl or phenyl, which areoptionally substituted by fluorine, chlorine, bromine or bystraight-chain or branched alkyl having up to 4 carbon atoms, D and Eare identical or different and representhydrogen, fluorine, chlorine,bromine or trifluoromethyl, Z represents oxygen, R¹ representscyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or representsstraight-chain or branched alkyl having up to 6 carbon atoms, R²represents hydrogen or methyl, R³ represents phenyl and R⁴ representsthe group --CH₂ --OH,or a salt thereof.
 4. Bicyclic heterocycliccompound according to claim 1 wherein such compound is2-cyclopentyl-N-(2-hydroxy-1(R)-phenylethyl)-2-4-(2-methyl-4-oxo-4H-quinazolin-3yl-methyl)phenyl!acetamide of theformula ##STR262## and salts thereof.
 5. A composition for the treatmentof atherosclerosis comprising an amount effective therefore of acompound or salt thereof according to claim 1 and a pharmacologicallyacceptable diluent.
 6. The method of treating atherosclerosis in apatient in need thereof which comprises administering to such patient anamount effective therefore of a compound or salt thereof according toclaim 1.